title: Superacid synthesized tertiary benzenesulfonamides and benzofuzed sultams act as selective hCA IX inhibitors: toward understanding a new mode of inhibition by tertiary sulfonamides.
abstract: A series of tertiary (fluorinated) benzenesulfonamides was synthesized in superacid HF-SbF5. To circumvent the problem of the in situ iminium ion formation, proved by low temperature NMR experiments, a tandem superacid catalysed cross-coupling reaction was employed to synthesize the benzofuzed sultams analogues. These tertiary benzenesulfonamides were tested as inhibitors of human carbonic anhydrases (hCAs, EC 4.2.1.1). These compounds did not inhibit the widespread off target hCA II isoform and showed strong selectivity toward tumor-associated carbonic anhydrase isoform IX. A dramatic effect of the electronic and structural shape of the inhibitors on selectivity was demonstrated, confirming the non-zinc-bonding mode of inhibition of this class of sulfonamides. This work allowed identifying a highly selective hCA IX inhibitor lead in this series.
authors.affiliation: Superacid group in "Organic Synthesis" team - Université de Poitiers, CNRS UMR 7285 IC2MP; 4, avenue Michel Brunet F-86022 Poitiers Cedex, France. sebastien.thibaudeau@univ-poitiers.fr.
authors.forename: Benoît
authors.initials: B
authors.lastname: Métayer
authors.forename: Agnès
authors.initials: A
authors.lastname: Martin-Mingot
authors.forename: Daniella
authors.initials: D
authors.lastname: Vullo
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Sébastien
authors.initials: S
authors.lastname: Thibaudeau
mesh_terms: D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases